Disease modeling

Disease modeling using human pluripotent stem cells (hiPSC)

LUMC is a major center in the Netherlands for the generation of hiPSC lines from patients. These cells can form any cells of the body and have the same genetic make-up as the donor. They can be genetically manipulated so that genetic mutations can be corrected, or disease mutations introduced into a healthy hiPSC line. Protocols have been developed and tested to create many cell types, including from the heart, brain, blood vessels, cells of the lung, kidney, eye, cartilage or bone, skeletal muscle, pancreas, and the reproductive and immune systems. This provides us with information on relevant changes in cells and tissue caused by mutations, drugs, toxic compounds, bacteria, and viruses. In combination with omics analyses, (live) imaging, and electrophysiology, it helps identify disease targets for phenotypic correction and future therapies.

Creating realistic human tissue mimics using microfluidics

Living tissues in the body are complex 3D structures composed of different cell types, with blood and lymph vessels through which fluids flow. The tissues undergo spatial constraints that result in pressure and load, and in the case of muscle, contraction, and relaxation in response to (patho)physiological stimuli. To create realistic tissue models, it’s important to include at least some of these parameters. This is done in Organ-on-Chip devices (OoCs) and LUMC is one of a few centers in the Netherlands specialized in the use of OoCs to address biological questions on human tissue (dys)function based on stem cells. Heart-, lung-, eye-, brain-, lymph- and blood vessels-on chip are already available or presently under development.

Disease modelling using (primary) human cells

Disease modeling is also done by Regenerative Medicine researchers using (primary) human cells to mimic (development of) pathophysiological conditions and investigate the underlying molecular mechanisms of disease as well as cross-talk between different cell types, for instance, islet cells with non-islet cells, endothelial cells with immune cells, in the context of type 1 diabetes.

To study osteoarthritis, Regenerative Medicine researchers use ex vivo cultures of osteochondral explants. This system models the disease because external triggers such as mechanical stress induce osteoarthritis features, allowing drug testing.

New models can also be generated by the conditional immortalization of primary human cells. Regenerative Medicine scientists have demonstrated this is possible for atrial myocytes. The approach is currently being extended to all other cell types in the human heart, as well as cells of other organs. The expectation is that this will make a human cell library available for disease modeling and testing new therapeutic strategies. Combined with the hiPSC technology, not only will these strategies create next-generation human models of disease, but may also contribute to reducing the use of animals in this area of biomedical research.

Functional analysis of gene therapies

LUMC has several focus areas in gene therapy that range from novel vectors for delivering gene constructs to mRNA-based approaches. Advanced (humanized) transgenic mouse models are used in addition to standard laboratory mouse strains and human tissues or (stem) cell models. Diseases include inherited skeletal muscle conditions like dystrophies (based on human cells where mouse models are not available, or the gene doesn’t exist), and inherited and acquired cardiomyopathies.

Ex Situ perfusion of whole organs to study disease and drug-drug interactions

The organ preservation and regeneration unit at LUMC has the capacity to place whole organs on ex situ machine perfusion devices under (near) physiologic conditions. Diseased livers with cirrhosis of varying etiology and/or hepatocellular carcinoma can be placed on the device and studied. In addition, therapeutic interventions (including stem cells) are delivered in this type of model to investigate grafting efficiency and drug-drug interactions in a whole organ environment.